Reminder of important clinical lesson
Case report
1
Serviço de Endocrinologia,
Universidade de Lisboa
Faculdade de Medicina, Lisboa,
Portugal
2 their plasma concentrations are low due to hepatic
Hospital de Santa Maria,
Serviço de Doenças Infecciosas,
Centro Hospitalar Lisboa Norte
EPE, Lisboa, Portugal
3
Hospital de Santa Maria,
Serviço de Reumatologia e
Doenças Ósseas Metabólicas,
Centro Hospitalar Lisboa Norte
EPE, Lisboa, Portugal
4
Unidade de Investigação em
Reumatologia, Instituto de
Medicina Molecular, Lisboa,
Portugal
5
Hospital de Santa Maria,
Serviço de Endocrinologia,
Centro Hospitalar Lisboa Norte
EPE, Lisboa, Portugal
Correspondence to
Professor Sónia do Vale;
​sonia.​vale@​chln.​min-​saude.​pt
Accepted 23 April 2020
© BMJ Publishing Group
Limited 2020. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
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by BMJ.
To cite: Figueiredo J,
Serrado M, Khmelinskii N,
et al. BMJ Case Rep
2020;13:e233712.
doi:10.1136/bcr-2019-
233712
Iatrogenic Cushing syndrome and multifocal
osteonecrosis caused by the interaction between
inhaled fluticasone and ritonavir
Joana Figueiredo,1 Margarida Serrado,2 Nikita Khmelinskii,3,4 Sónia do Vale  ‍ ‍1,5
SUMMARY and cytochrome P450 (CYP450) inhibitors and its
Inhaled corticosteroids are generally considered safe potential severe consequences.
and do not usually lead to systemic adverse events since
Case presentation
metabolism by the cytochrome P450 3A4. However, A 40-­ year-­
old man with well-­ controlled HIV1
when associated with inhibitors of this cytochrome, infection (CD4+ T cell count of 518 cells/mm3
such as ritonavir, they may lead to iatrogenic and undetectable HIV1 RNA) presented to the
Cushing syndrome by the systemic accumulation of Endocrinology Department due to weight gain
corticosteroids and consequent suppression of the and abdominal and limb striae. His medical back-
hypothalamic-­pituitary-­adrenal axis. We present a ground included COPD and alcohol, tobacco and
case of iatrogenic Cushing syndrome complicated by past intravenous heroin abuse. HIV1 infection was
multifocal osteonecrosis in a patient with HIV infection diagnosed when he was 25 years old and treatment
on antiretroviral therapy with protease inhibitors with lopinavir/ritonavir 400 mg/100 mg two times
boosted with ritonavir, after the association of inhaled per day, saquinavir 1000 mg two times per day
fluticasone. This clinical case highlights a relevant and tenofovir 300 mg one time a day was started
interaction between corticosteroids and inhibitors of at the age of 33 years (CD4+ T cell count of 78
the cytochrome P450 and the severe consequences that cells/mm3 and HIV1 RNA viral load of 2300 copies,
may occur. log10 3.38, before ART). At 35 years of age inhaled
therapy with fluticasone/salmeterol 250  µg/50 µg
two times per day and tiotropium bromide 18 µg
one time a day was added for COPD. One year
Background
later, he developed avascular necrosis of the right
Ritonavir is a protease inhibitor that is often used in
femoral head and underwent total hip arthroplasty.
combination with other antiretrovirals in the treat-
The patient was first observed in January 2013,
ment of HIV infection. It is a potent inhibitor of the
5 years after the initiation of inhaled corticosteroid
hepatic cytochrome P450 3A4 (CYP3A4) acting as
therapy. He reported a gradual increase in abdom-
a booster and allowing other antiretroviral agents
inal and cervical volume, 15 kg weight gain over the
metabolised by this cytochrome to reach higher
plasma concentrations. This enables a decrease in
pill burden and an increase of the dosing intervals,
improving patient adherence and decreasing treat-
ment failure.1
Inhaled corticosteroids are drugs widely used
in the treatment of asthma, allergic rhinitis and
chronic obstructive pulmonary disease (COPD).
They are considered safe due to the low plasma
concentrations they reach after metabolism by the
CYP3A4. When combined with potent inhibitors of
this cytochrome, there may be a significant increase
in plasma corticosteroid levels.1 This may cause
iatrogenic Cushing syndrome, suppression of the
hypothalamic–pituitary–adrenal (HPA) axis, acute
adrenal insufficiency in case of abrupt corticoste-
roid withdrawal, as well as hypertension, osteopo-
rosis and avascular necrosis.1–5
We report a case of iatrogenic Cushing syndrome
and multifocal osteonecrosis in a patient with
HIV1 infection on a ritonavir-­ boosted antiretro-
viral therapy (ART) and COPD treated with fluti-
casone. It is intended to emphasise the importance Figure 1  Centripetal obesity and wide and divergent
of the interaction between inhaled corticosteroids purpuric striae.
Figueiredo J, et al. BMJ Case Rep 2020;13:e233712. doi:10.1136/bcr-2019-233712 1
Reminder of important clinical lesson

Table 1  Laboratory findings evolution

With corticosteroids Without corticosteroids (since Jul 2013)
January 2013, September February 2014, September March 2015, December April 2017,
Normal range 40 years old* May 2013 2013 41 years old 2014 42 years old 2015 44 years old
ACTH 0–46 <5 <5 10.5 21.4 16 17.9 26.4
(pg/mL)
Serum cortisol 4.3–23 0.4 0.4 2.6 12.2 9.1 10.4 20.5
(μg/dL)
Urinary cortisol 55.5–286 10 9 13 84 194
(μg/24 hours)
FSH (U/L) 1.4–18.1 36.6 26.3 25.0 27.2 30.0
LH (U/L) 1.5–9.3 12.7 12.7 13.7 15.9 13.0
Total testosterone 240–830 465 309 290 337
(ng/dL)
Free testosterone 6.6–23 2.0 5.4 5.1 5.6 9.3
(pg/mL)
SHBG 10–57 64.2 67.6 54.9 69.0
(nmol/L)
*At this time the diagnosis of exogenous Cushing syndrome was made, and the patient started reducing the dose of corticosteroids.
ACTH, adrenocorticotropic hormone; FSH, follicle-­stimulating hormone; LH, luteinising hormone; SHBG, sexhormone-­binding globulin.

previous 6 months, appearance of abdominal and limb striae,
gynecomastia, ankle oedema, erectile dysfunction and humoral
lability. On physical examination he was noted to have a plethoric
‘full moon’ facies, centripetal obesity (body mass index (BMI) of
35 kg/m2), dorsocervical fat pads, proximal muscular atrophy,
wide and divergent purpuric striae in the abdomen, arms and
thighs (figure 1) and high blood pressure.
cortisol is endogenous or administered. Other corticosteroids
may also interfere with these measurements.
Treatment
After the diagnosis, the dose of fluticasone was progressively
reduced. The patient also started antihypertensive and statin
therapy.

Outcome and follow-up

Investigations
Laboratory evaluation revealed low serum and urinary cortisol
with low serum adrenocorticotrophic hormone (ACTH) concen-
trations, indicating suppression of the HPA axis. Furthermore,
dyslipidaemia and hypergonadotropic hypogonadism were
detected (table 1). A bone density scan (BDS) revealed low bone
mineral density (Z-­score of the lumbar spine of −3.6), compat-
ible with osteoporosis.
Differential diagnosis
Presented with these findings, a diagnosis of exogenous/iatro-
genic Cushing syndrome secondary to inhaled fluticasone was
made.
Regarding the differential diagnosis of Cushing syndrome in
patients undergoing ART, it is important to consider ART-­related
lipodystrophy. In lipodystrophy, there is a metabolic dysregula-
tion that leads to weight gain, central fat distribution and dors-
ocervical fat pads. In the case at hand, the presence of rapid
weight gain, purpuric abdominal striae and facial plethora all
point to the Cushing syndrome. In contrast, HIV-­associated lipo-
dystrophy is associated with more evident peripheral muscular
atrophy than Cushing syndrome.1–3 Laboratory evaluation clar-
ifies the diagnosis since there are abnormal concentrations of
cortisol and ACTH in the Cushing syndrome.
We must also distinguish between iatrogenic and endogenous
Cushing syndrome. When Cushing syndrome is iatrogenic, the
endogenous synthesis of cortisol is supressed due to the negative
feedback exerted by the excess of exogenous corticosteroids on
the hypothalamus and the pituitary gland. Suppressed ACTH
and cortisol concentrations mean that the source of corticoste-
roids is exogenous, representing therefore an iatrogenic Cushing
syndrome. However, if the patient is taking hydrocortisone, the
cortisol measurements do not distinguish whether the source of
2 Figueiredo J, et al. BMJ Case Rep 2020;13:e233712. doi:10.1136/bcr-2019-233712
After 4 months of corticosteroids at a halved dose, the patient
continued to demonstrate HPA axis suppression and the decision
was made to continue weaning fluticasone. Eventually the fluti-
casone/salmeterol was totally ceased and replaced by indacaterol
150 µg one time a day in July 2013.
In September 2013, after 3 months without corticosteroids,
the patient had a less ‘full moon’ facies, no oedema, less purpuric
striae and a 6 kg weight loss over a 9 month period (BMI of 33 kg/
m2). He reported an improvement of erectile dysfunction. From
the respiratory point of view, the patient remained stable without
the need of steroid therapy. Serum and urinary cortisol were
closer to reference values and ACTH was not suppressed (table 1).
Approximately 1 year after corticosteroid cessation, the patient
complained of left knee pain and claudication. Plain radiography
of the knees revealed bilateral sclerotic lesions in a serpiginous
pattern and the diagnosis of aseptic necrosis with subchondral
bone collapse of the medial left femoral condyle was confirmed
by magnetic resonance imaging (figure 2). Conservative treat-
ment that included protected weightbearing with crutches, non-­
steroidal anti-­inflammatory drugs and alendronate 70 mg weekly
for 2 years ensured full symptomatic relief and no radiographic
progression on long-­term follow-­up.
There was a gradual improvement of the Cushing syndrome
signs as well as laboratory abnormalities, with normalisation of
the HPA axis function. Reassessment BDS revealed improvement
of the bone mineral density. Laboratory tests performed at the
same time revealed total testosterone and free testosterone levels
within normal range, while maintaining high follicle-­stimulating
hormone and luteinising hormone(table 1).
Discussion
The presented clinical case describes an iatrogenic Cushing
syndrome complicated by multifocal osteonecrosis resulting

Figure 2  Resonance imaging of the left knee demonstrating aseptic
necrosis with subchondral bone collapse of the medial left femoral
condyle.
from a drug interaction between ritonavir and fluticasone. There
are already a number of published articles describing the conse-
quences of the interaction between these two drugs.3In 2013,
a Review article found 51 published case reports regarding
adverse effects with the use of inhaled or/and intranasal cortico-
steroids and protease inhibitors, most of which (approximately
86%) were related to the association between fluticasone and
ritonavir.3 The most common reported symptoms were ‘full
moon’ facies, facial hirsutism, central obesity and weight gain,
dorsocervical fat pads, striae and easy bruising.3 There were
five cases of osteoporosis and one case of osteonecrosis of both
hips.3 5 However, despite the presence of these well-­documented
cases of iatrogenic Cushing syndrome, similar reports continue
to emerge.2 6 7
Ritonavir, being a potent inhibitor of the hepatic CYP3A4,
increases the concentration of other protease inhibitors included
in the combined ART and enhances HIV treatment success.
However, ritonavir can also increase corticosteroids concen-
trations, as they are substrates of the CYP3A4. Therefore, this
interaction can result in impaired metabolism and systemic
corticosteroid accumulation, adrenal suppression and Cushing
syndrome.1 2
Compared with other inhaled corticosteroids, fluticasone
exhibits the most suppressive impact on the HPA axis. This is due
to its pharmacokinetic properties, such as higher glucocorticoid
receptor binding affinity, longer half-­life and higher lipophilicity,
allowing a greater volume of distribution. These characteristics
facilitate the systemic accumulation of fluticasone and make it
more susceptible to drug interactions.1–3
The most common clinical feature of the Cushing syndrome
is weight gain with central fat distribution. Other typical mani-
festations include, ‘full moon’ facies, facial plethora, dorsocer-
vical fat pads (‘buffalo hump’), skin atrophy, acne, easy bruising
and purple striae. Hirsutism (in women), proximal myopathy,
insulin resistance, dyslipidaemia, hypertension, immunosup-
pression, psychiatric disorders and osteopenia or osteoporosis
are also common.2 8 9 Given the reported clinical case, it is also
important to note that hypogonadism, HIV infection, ART and
tobacco and alcohol abuse may also contribute to a decrease in
bone mineral density.10 11
There are other important consequences of hypercortisolism,
namely gonadal dysfunction and aseptic osteonecrosis. Gonadal
dysfunction occurs in more than 75% of patients with Cushing
syndrome and is usually hypogonadotropic.9 11 However, the
patient presented with hypergonadotropic hypogonadism and
several contributing factors transpire: chronic alcoholism, the
use of certain illicit drugs and HIV infection.11 12
Figueiredo J, et al. BMJ Case Rep 2020;13:e233712. doi:10.1136/bcr-2019-233712
Reminder of important clinical lesson
As mentioned, the patient developed avascular necrosis of
the right femoral head and, approximately 5 years after, of both
knees. Although infrequent, avascular necrosis may have been
the first manifestation of the Cushing syndrome.13 Multiple
other risk factors for avascular necrosis were also present: alco-
holism, hypertriglyceridemia, HIV infection and smoking.4 5 13
Therefore, we cannot conclude that hypercortisolism was an
isolated cause of multifocal osteonecrosis, but it probably was
a significant contributing factor. To our knowledge, only
two other cases of avascular necrosis have been reported as
being attributed to the interaction between fluticasone and
ritonavir.4 5
After the diagnosis of iatrogenic Cushing syndrome due to the
interaction between inhaled corticosteroids and ritonavir, treat-
ment involves either replacing ritonavir with another antiretro-
viral that does not inhibit the CYP3A4 or changing fluticasone
while maintaining ritonavir. Fluticasone can be substituted for
another less potent inhaled corticosteroid and less dependent
on CYP450 metabolism (eg, beclomethasone), a leukotriene
antagonist (eg, montelukast) or an anticholinergic agent (eg,
tiotropium). It is unclear if significant dose reductions of the
intranasal/inhaled corticosteroid will result in the complete reso-
lution of the clinical picture since accounts of this interaction
have been reported at low doses.2 3
If treatment with another inhaled corticosteroid is started, the
lowest possible dose should always be administered and the clin-
ical course should be closely monitored considering case reports
of iatrogenic Cushing syndrome due to other inhaled cortico-
steroids.1 3
If corticosteroid therapy is to be suspended, this should always
be done progressively because of the risk of acute adrenal insuf-
ficiency. The exogenous corticosteroids supress the HPA axis.
With an abrupt cessation of exogenous corticosteroids, the HPA
axis is incapable of rapidly producing endogenous cortisol,
which results in acute adrenal insufficiency.6
In conclusion, corticosteroid therapy even in ‘non-­systemic’
formulations, namely intranasal or inhaled, should be avoided
in patients receiving ritonavir (or another CYP3A4 inhibitor). If
treatment with an inhaled corticosteroid is imperative, flutica-
sone should not be the first therapeutic option.
Learning points
►► Ritonavir is a potent cytochrome P450 3A4 inhibitor acting
as a booster of other drugs metabolised via this cytochrome,
such as corticosteroids.
►► Co-­administration of ritonavir (or other potent cytochrome
P450 (CYP450) inhibitors) with corticosteroids, including
intranasal or inhaled formulations, may induce systemic
corticosteroid accumulation, Cushing syndrome, adrenal
insufficiency, hypertension, osteoporosis and avascular
necrosis.
►► Compared with other inhaled corticosteroids, fluticasone
is the most susceptible to drug interactions with CYP450
inhibitors while beclomethasone is probably the safest
option.
►► Treatment options for the iatrogenic Cushing syndrome
induced by this interaction include replacing ritonavir with
another antiretroviral or slow tapering of fluticasone and
replacing it with beclomethasone, a leukotriene antagonist or
an anticholinergic agent.
3
 Reminder of important clinical lesson
Contributors  MS, NK and SdV were involved in the treament of the presented
patient. JF wrote the manuscript with the help from SdV, NK and MS. All authors
contributed to the final version of the manuscript.
Funding  The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests  None declared.
Patient consent for publication  Obtained.
Provenance and peer review  Not commissioned; externally peer reviewed.
Open access  This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,
and license their derivative works on different terms, provided the original work
is properly cited and the use is non-­commercial. See: http://​creativecommons.​org/​
licenses/​by-​nc/​4.​0/.
ORCID iD
Sónia do Vale http://​orcid.​org/​0000-​0001-​9287-​4095
10 Ashby J, Goldmeier D, Sadeghi-­Nejad H. Hypogonadism in human immunodeficiency
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4 Figueiredo J, et al. BMJ Case Rep 2020;13:e233712. doi:10.1136/bcr-2019-233712